Case–control association analysis of polymorphisms in the delta-opioid receptor, OPRD1, with cocaine and opioid addicted populations

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Abstract

Background

Addiction susceptibility and treatment responsiveness are greatly influenced by genetic factors. Sequence variation in genes involved in the mechanisms of drug action have the potential to influence addiction risk and treatment outcome. The opioid receptor system is involved in mediating the rewarding effects of cocaine and opioids. The μ-opioid receptor (MOR) has traditionally been considered the primary target for opioid addiction. The MOR, however, interacts with and is regulated by many known MOR interacting proteins (MORIPs), including the δ-opioid receptor (DOR).

Methods

The present study evaluated the contribution of OPRD1, the gene encoding the DOR, to the risk of addiction to opioids and cocaine. The association of OPRD1 polymorphisms with both opioid addiction (OA) and cocaine addiction (CA) was analyzed in African American (OA n = 336, CA n = 503) and European American (OA n = 1007, CA n = 336) populations.

Results

The primary finding of this study is an association of rs678849 with cocaine addiction in African Americans (allelic p = 0.0086). For replication purposes, this SNP was analyzed in a larger independent population of cocaine addicted African Americans and controls and the association was confirmed (allelic p = 4.53 × 10−5; n = 993). By performing a meta-analysis on the expanded populations, the statistical evidence for an association was substantially increased (allelic p = 8.5 × 10−7) (p-values non-FDR corrected).

Conclusion

The present study suggests that polymorphisms in OPRD1 are relevant for cocaine addiction in the African American population and provides additional support for a broad role for OPRD1 variants in drug dependence.

Introduction

Twin and family studies suggest that a large percentage of risk for both opioid addiction (OA; Arvidsson et al., 1995, Karkowski et al., 2000, Kendler et al., 2003, Merikangas et al., 1998, Tsuang et al., 1998) and cocaine addiction (CA; Karkowski et al., 2000, Kendler et al., 2000, Kendler and Prescott, 1998, Zhang et al., 2006) is influenced by genetic factors (reviewed in Kreek et al., 2005, Saxon et al., 2005, Yuferov et al., 2010). Understanding which genes influence addiction susceptibility could improve treatment options and patient care. However, identification of causal genes has been difficult due to the polygenic inheritance underlying addictive behavior.

Opioid receptors have been the focus of addiction research due to the involvement of these receptors in drug reward pathways. The most widely studied members of the opioid receptor family are the μ-opioid receptor (MOR), δ-opioid receptor (DOR) and κ-opioid receptor (KOR), which bind endogenous opioid peptides such as β-endorphin, endomorphines, enkephalins, and dynorphins (reviewed in Zaki et al., 1996). Stimulation of opioid receptors inhibits adenylate cyclase, increases potassium conductance, decreases calcium conductance, and activates MAP Kinase pathways (Childers, 1991, reviewed in Law et al., 2000). The rewarding effects of drug use are mediated by MOR and DOR activation, whereas KOR activation is associated with aversion (Di Chiara and Imperato, 1988, Herz, 1998). Furthermore, DOR is thought to be involved in analgesia, morphine tolerance and mood regulation such as anxiety and depression (Filliol et al., 2000, Perrine et al., 2006, Zhu et al., 1999).

The opioid receptor system, and particularly MOR, has been studied extensively for its role in OA (Matthes et al., 1996, Sora et al., 1997) and CA (Becker et al., 2002, Hall et al., 2004, Hummel et al., 2006). Several studies have analyzed the influence of single nucleotide polymorphisms (SNPs) in OPRM1, the gene encoding MOR, on risk for drug addiction, but the results have been inconclusive (Bart et al., 2004, Crowley et al., 2003, Hoehe et al., 2000, Smith et al., 2005, Szeto et al., 2001, Tan et al., 2003, Zhang et al., 2006). Although MOR is considered the primary target for the rewarding effects of addiction, there are many known MOR interacting proteins (MORIPs) that may modulate MOR function. One of these MORIPs is DOR (Milligan, 2005), suggesting that genetic variation in OPRD1, the gene encoding DOR, may affect susceptibility to drug addiction.

Two coding variants of OPRD1 have been studied for association with alcohol and drug addiction: rs1042114 (G80T) and rs2234918 (T921C). Mayer et al. found rs2234918 to be associated with heroin addiction in a German population (Mayer et al., 1997). rs1042114 was associated with OA and a 6 SNP haplotype which included rs1042114 and rs2234918 was associated with alcohol, cocaine, and opioid addiction in a cohort of European-Americans (Zhang et al., 2008). An additional study identified an association of three OPRD1 intronic SNPs with heroin addiction in EA (412 cases vs. 184 controls) and also reported a combined effect of OPRD1 and OPRM1 on heroin addiction (Levran et al., 2008). A recent study of 1459 case and 1495 controls found two intronic OPRD1 SNPs (rs2236857 and rs581111) to be associated with risk for heroin addiction (Nelson et al., 2012). However, no evidence was found for an association of either SNP in additional heroin- and alcohol-addicted German populations (Franke et al., 1999), heroin-addicted Chinese individuals (Xu et al., 2002), or alcohol-addicted Taiwanese Hans (Loh el et al., 2004). Xuei et al. also reported that OPRD1 variants were not associated with alcohol addiction or OA in a study of 1923 European-American subjects from 219 multiplex alcohol-addicted families (83 individuals demonstrating OA; Xuei et al., 2007).

Currently, additional research is needed to understand the role of OPRD1 in both opioid and cocaine addiction. The present study was designed to genotype a comprehensive panel of SNPs within OPRD1 and test for association with both OA and CA populations across European-American (EA) and African-American (AA) ancestries.

Section snippets

Cases

DNA samples were requested and acquired through the NIDA Center for Genetic Studies in conjunction with Washington University and Rutgers University Cell and DNA Repository (RUCDR). OA (EA: n = 1007; male 65.6%; AA: n = 336 male 71.4%) and CA subjects (EA: n = 336; male 50.3%; AA: n = 503; male 52.1%) of EA and AA descent met DSM-IV criteria for addiction (Table 1). AA CA samples from RUCDR are labeled as “Group 1” in subsequent analysis. DNA samples were transferred to 96-well stock plates and diluted

European-American Population Genotypic and Allelic Associations

In the EA population, no significant allelic associations were found for OA; however, rs10753331 was nominally significant for genotypic association with OA (p = 0.02; Table 2). Sex-specific analyses showed nominal association in males with the non-synonymous SNPs rs1042114 (p = 0.008), rs2236855 (p = 0.02), and rs10753331 (p = 0.01). Several haplotype blocks had nominally significant associations with OA as well (Supplemental data Table 12

Discussion

The present study focused on the association between OPRD1 genetic variants and cocaine and opioid addiction in EA and AA populations. In the EA population, a nominally significant association of the synonymous SNP rs2234918 with CA was observed, as well as sex-specific nominal associations for several other OPRD1 SNPs. In the EA population with OA, a nominal sex-specific association of the non-synonymous SNP rs1042114 was identified. Associations of rs581111 with OA and rs2236855 with CA in

Role of funding source

This work was supported by the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Training Program in Neuropsychopharmacology (T32MH014654, P.I.: I. Lucki) and a NIDA Distinguished International Scientist Award (MV). Financial support is gratefully acknowledged from NIDA grant P20DA025995 (P.I.: W. Berrettini), the Veterans Administration Mental Illness Research Education and Clinical Center MIRECC) at the Philadelphia VAMC (David Oslin, MD, PI) and NIDA

Contributors

The authors LMAL, MV, TKC, GAD, and WB were responsible for the study concept and design. LMAL, MV, AZ, CY were responsible for the acquisition of genotype data. LMAL, TKC, RC, GAD conducted the bioinformatic and statistical analysis. LMAL, WHB, TNF, FWL, GAD, KMK, CPO, HMP, DWO and HH were responsible for sample acquisition and characterization. RC, LMAL and WB drafted the manuscript. All authors critically reviewed content and approved final version for publication.

Conflict of interest

The authors report no biomedical financial interests or potential conflicts of interest.

Acknowledgments

We would like to acknowledge NIDA's Center for Genetic Studies in conjunction with Washington University and Rutgers University Cell & DNA Repository for providing DNA samples collected from the following studies and investigators: Opioid Samples: Addictions: Genotypes, Polymorphisms and Function, Mary Jeanne Kreek, M.D.; Genetics of Opioid Dependence, Joel Gelernter, M.D., Kathleen Brady, M.D., Ph.D., Henry Kranzler, M.D., Roger Weiss, M.D.; Opioid Dependence, Wade Berrettini, M.D., Ph.D.

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    Supplementary material can be found by accessing the online version of this paper. Please see Appendix A for more information.

    1

    These authors contributed equally to this work.

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